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Definitions

• the present invention relates to 2,5-disubstituted thiazol-4-one derivatives and to the use thereof for producing medicaments, to processes for their preparation and to medicaments comprising these compounds.
• a suitable starting point for the treatment of pain, especially of neuropathic pain is the vanilloid receptor of subtype 1 (VR1/TRPV1), which is frequently also referred to as the capsaicin receptor.
• This receptor is stimulated, inter alia, by vanilloids, for example capsaicin, heat and protons, and plays a central role in the development of pain.
• vanilloids for example capsaicin, heat and protons
• it is of significance for a multitude of further physiological and pathophysiological processes, for example migraines; depressions; neurodegenerative disorders; cognitive disorders; states of anxiety; epilepsy; coughing; diarrhea; pruritus; disorders of the cardiovascular system; disorders of food intake; medicament dependence; medicament abuse and especially urine incontinence.
• 2,5-disubstituted thiazol-4-one derivatives of the general formula I specified below are suitable for controlling pain and have an excellent affinity for the vanilloid receptor of subtype 1 (VR1/TRPV1 receptor), and are therefore suitable especially for prophylaxis and/or treatment of disorders or diseases which are mediated at least partly by vanilloid receptors 1 (VR1/TRPV1).
• the present invention therefore provides for the use of at least one 2,5-disubstituted thiazol-4-one derivative of the general formula I
• Aliphatic radicals in the context of this invention include acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and also unsubstituted or monosubstituted or polysubstituted identically or differently, having preferably from 1 to 20 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), more preferably from 1 to 12 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12), most preferably from 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) carbon atoms, i.e.
• Alkenyls have at least one C—C double bond and alkynyls have at least one C—C triple bond.
• aliphatic radicals may be selected from the group which comprises methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosanyl, ethenyl(vinyl), ethynyl,
• the aforementioned aliphatic radicals may preferably have 1, 2 or 3 heteroatoms selected from the group comprising oxygen, sulfur and nitrogen, i.e. —N(H)— and —N(C 1-6 -alkyl).
• Examples of aliphatic radicals which have 1, 2 or 3 heteroatoms include —(CH 2 )—(CH 2 )—O—CH 3 , —(CH 2 )—(CH 2 )—(CH 2 )—O—CH 3 , —(CH 2 )—(CH 2 )—(CH 2 )—N(C 2 H 5 )—(C 2 H 5 ), —(CH 2 )—(CH 2 )—S—CH 3 , —(CH 2 )—(CH 2 )—(CH 2 )—S—CH 3 , —(CH 2 )—(CH 2 )—(CH 2 )—N(CH 3 )—(CH 3 ) and —(CH 2 )—O—CH 3 .
• substituted in connection with aliphatic radicals, the term “substituted”—unless defined differently elsewhere in the description or in the claims—in the context of this invention is understood to mean single or multiple substitution, preferably mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa- or nonasubstitution, of one or more hydrogen atoms by, for example, F, Cl, Br, I, —CN, —NO 2 , —OH, —SH and —NH 2 , where the multiple substitution is multiple, for example double or triple, either on different or on the same atoms, for example triple on the same carbon atom as in the case of —CF 3 or —CH 2 CF 3 , or on different positions as in the case of —CH(OH)—CH ⁇ CCl—CH 2 Cl.
• Particularly preferred substituted aliphatic radicals are —CF 3 , —C 2 F 5 , —CH 2 F, —CHF 2 , —CF 2 —CF 2 —CF 3 , —CH 2 —Cl, —CH 2 —Br, —CH 2 —CH 2 —Cl, —CH 2 —CH 2 —Br, —CH 2 —CH 2 —CH 2 —Br and —CH 2 —CH 2 —CH 2 —CH 2 —Cl.
• Cycloaliphatic radicals in the context of this invention are cyclic saturated or unsaturated hydrocarbon radicals having preferably 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, more preferably 3, 4, 5, 6, 7 or 8 carbon atoms, where each radical may be unsubstituted or monosubstituted or polysubstituted identically or differently. Cycloaliphatic radicals may preferably have 1, 2, 3, 4 or 5 heteroatoms selected independently from the group consisting of oxygen, nitrogen (NH) and sulfur.
• a mono- or polycyclic ring system is understood in the context of the present invention to mean mono-polycyclic hydrocarbon radicals which may be saturated or unsaturated and optionally have 1, 2, 3, 4 or 5 heteroatom(s) as ring member(s), which are each independently selected from the group consisting of oxygen, nitrogen and sulfur.
• Such a mono- or polycyclic ring system may, for example, be fused to an aryl radical or a heteroaryl radical.
• a polycyclic ring system for example a bicyclic ring system
• the different rings may each independently have a different degree of saturation, i.e. be saturated or unsaturated.
• a polycyclic ring system is preferably a bicyclic ring system.
• aryl radicals which are fused to a mono- or polycyclic ring system include [1,3]-benzodioxolyl, [1,4]-benzodioxanyl, [1,2,3,4]-tetrahydronaphthyl, [1,2,3,4]-tetrahydroquinolinyl, [1,2,3,4]-tetrahydroquinazolinyl and [3,4]-dihydro-2H-1,4-benzoxazinyl.
• substituted in connection with cycloaliphatic radicals and mono- or polycyclic ring systems, the term “substituted”—unless defined differently elsewhere in the description or in the claims—in the context of this invention is understood to mean the single or multiple substitution, preferably the mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa- or nonasubstitution, of one or more hydrogen atoms by, for example, oxo ( ⁇ O), thioxo ( ⁇ S), F, Cl, Br, I, —CN, —CF 3 , —SF 5 , —OH, —O—C 1-5 -alkyl, —NH 2 , —NO 2 , —O—CF 3 , —S—CF 3 , —SH, —S—C 1-5 -alkyl, —C 1-5 -alkyl, —C( ⁇ O)—OH, —C( ⁇ O)—
• aryl radical should be understood to mean a radical which is preferably selected from the group which comprises phenyl, naphthyl, phenanthrenyl and anthracenyl, and is unsubstituted or mono- or polysubstituted identically or differently.
• Aryl is more preferably an unsubstituted or monosubstituted or identically or differently polysubstituted, for example bi-, tri-, tetra- or pentasubstituted, phenyl, 1-naphthyl or 2-naphthyl.
• heteroaryl radicals are those heterocycles which are heteroaromatic.
• Heteroaryl radicals are preferably 5- to 14-membered, i.e. 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered, and have preferably 1, 2, 3, 4 or 5 heteroatoms selected independently from the group comprising oxygen, nitrogen and sulfur.
• Each heteroaryl radical may be present unsubstituted or monosubstituted or polysubstituted for example bi-, tri-, tetra- or pentasubstituted, identically or differently.
• heteroaryl radicals in the context of the invention include thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyranyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinazolinyl, quinolinyl, isoquinolinyl, benzimidazolinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzo[2,1,3]thiadiazolyl, [1,2,3]-benzothiadiazolyl, [2,1,3]-benzoxadiazolyl and [1,2,3]-benzoxadiazolyl.
• substituted in the context of this invention is understood to mean the single or multiple substitution, for example mono-, di-, tri-, tetra- or pentasubstitution, of one or more hydrogen atoms of the ring system by suitable substituents.
• suitable substituents are F, Cl, Br, I, —CN, —CF 3 , —SF 5 , —OH, —O—C 1-10 -alkyl, —O—C 1-10 -alkenyl, —NH 2 , —NO 2 , —O—CF 3 , —S—CF 3 , —SH, —S—C 1-5 -alkyl, —C 1-5 -alkyl, —C( ⁇ O)—OH, —C( ⁇ O)—O—C 1-5 -alkyl, —O—C( ⁇ O)—C 1-5 -alkyl, —NH—C 1-5 -alkyl, —N(C 1-5 -alkyl) 2 , —NH—C( ⁇ O)—O—C 1-5 -alkyl, —C( ⁇ O)—
• the aforementioned linear or branched alkylene, alkenylene or alkynylene groups preferably have from 1 to 5 carbon atoms, i.e. they are C 1-5 -alkylene, C 2-5 -alkenylene or C 2-5 -alkynylene groups, each of which may be unsubstituted or substituted by preferably 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of F, Cl, Br, —OH, —SH, —NH 9 , —CN, —NO 9 and phenyl, where the phenyl radical may preferably be substituted by 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl.
• Alkylene groups may more preferably be selected from the group consisting of —(CH 2 )—, —(CH 2 ) 2 —, —C(H)(CH 3 )—, —C(CH 3 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —C(H)(CH 3 )—(CH 2 )—, —C(H)(C 2 H 5 )—(CH 2 )—, —C(phenyl) 2 - and —C(H)(phenyl).
• An alkynylene group is more preferably a —C ⁇ C— group.
• inventive compounds which, in the FLIPR assay, in a concentration of 10 ⁇ M, have an inhibition of the Ca 2+ ion current in dorsal root ganglia of rats of at least 10%, preferably of at least 30%, more preferably of at least 50%, even more preferably of at least 70%, even more preferably of at least 90%, compared to the maximum achievable inhibition of the Ca 2+ ion current with capsaicin in a concentration of 10 ⁇ M.
• the Ca 2+ current is quantified with the aid of a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA), as described below.
• a Ca 2+ -sensitive dye Fluoro-4 type, Molecular Probes Europe BV, Leiden, the Netherlands
• FLIPR fluorescent imaging plate reader
• the present invention further provides for the use of at least one inventive 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, in each case, as appropriate, in the form of one of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of a mixture of stereoisomers, especially of the enantiomers and/or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and also, as appropriate, one or more pharmaceutically acceptable excipients, for producing a medicament for vanilloid receptor 1 (VR1/TRPV1) regulation, preferably for vanilloid receptor 1 (VR1/TRPV1) inhibition or for vanilloid receptor 1 (VR1/TRPV1) stimulation.
• VR1/TRPV1 vanilloid receptor 1
• VR1/TRPV1 vanilloid receptor 1
• VR1/TRPV1 vanilloid receptor 1
• the present invention further provides 2,5-disubstituted thiazol-4-one derivatives of the general formula Ia
• inventive compounds which, in the FLIPR assay, in a concentration of 10 ⁇ M, have an inhibition of the Ca 2+ ion current in dorsal root ganglia of rats of at least 10%, preferably of at least 30%, more preferably of at least 50%, even more preferably of at least 70%, even more preferably of at least 90%, compared to the maximum achievable inhibition of the Ca 2+ ion current with capsaicin in a concentration of 10 ⁇ M.
• the Ca 2+ current is quantified with the aid of a Ca 2+ -sensitive dye (Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA), as described below.
• a Ca 2+ -sensitive dye Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands
• FLIPR fluorescent imaging plate reader
• R 2a is as defined above, and the latter is optionally purified and/or isolated, and at least one compound of medium in the presence of at least one base, preferably in the presence of at least one metal hydride salt or of a metal alkoxide salt, more preferably in the presence of a metal hydride salt or of a metal alkoxide salt selected from the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, sodium ethoxide and potassium ethoxide, with at least one compound of the general formula LG-R 3a or of the general formula LG-R 7a or of the general formula LG-R 5a , in which LG is in each case a leaving group, preferably a halogen atom, more preferably a chlorine atom, and R 3a , R 5a and R 7a are each as defined above to give at least one compound of the general formula Ia in which R 2a is as defined above and
• reaction of compounds of the general formula IIa in which R 1a is an —NHR 5a group with compounds of the general formula R 6a —C( ⁇ O)—OH is effected preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, optionally in the presence of an organic base, preferably selected from the group consisting of triethylamine, 4,4-dimethylaminopyridine, pyridine and diisopropylethylamine, or of an inorganic base, at temperatures of preferably from ⁇ 70° C. to 100° C.
• a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures
• an organic base preferably selected from the group consisting
• reaction of compounds of the general formula IIa in which R 1a is an —NHR 5a group with compounds of the general formula R 6a —C( ⁇ O)—OH is effected preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, optionally in the presence of at least one coupling reagent, preferably selected from the group consisting of 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-ylmethylene]-N-methylme
• a process for preparing 2,5-disubstituted thiazol-4-one derivatives of the general formula Ia according to which at least one compound of the general formula R 1a —CN in which R 1a is as defined above with the exception of an NR 3a R 4a group, of an NR 5a —C( ⁇ O)—R 6a group and of an NR 7a —C( ⁇ O)—NR 8a R 9a group, is reacted in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol and n-butanol, in the presence of at least one organic base selected from the group consisting of triethylamine, pyridine, diisopropylamine and N-methylmorpholine or in pyridine as a reaction medium, with thioglycolic acid to give at least one compound of the general formula IIIa
• R 1a is as defined above with the exception of an NR 3a R 4a group, of an NR 5a —C( ⁇ O)—R 6a group and of an NR 7a —C( ⁇ O)—NR 8a R 9a group, and the latter is optionally purified and/or isolated; or at least one compound of the general formula H 2 N—C( ⁇ S)—NHR 1a in which R 1a is as defined above with the exception of an NR 3a R 4a group, of an NR 5a —C( ⁇ O)—R 6a group and of an NR 7a —C( ⁇ O)—NR 8a R 9a group, is reacted in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol and n-butanol, optionally in the presence of at least one organic base selected from the group consisting of triethylamine, pyridine, diisopropylamine and N-methylmorpholine, with chloroacetic acid to give at
• R 1a —CN, R—C( ⁇ O)—H, R 3a -LG, R 4a -LG, R 5a -LG, R 7a -LG, R 9a -LG, H 2 N—C( ⁇ S)—NHR 1a , R 6a —C( ⁇ O)-LG, R 6a —C( ⁇ O)—OH and R 8a —N ⁇ C ⁇ O are each commercially available on the market and can also be prepared by customary processes known to those skilled in the art.
• the above-described reactions may each be carried out under the customary conditions familiar to those skilled in the art, for example with regard to pressure or sequence of addition of the components.
• the process regime which is optimal under the particular conditions can be determined by the person skilled in the art by simple preliminary experiments.
• the intermediates and end products obtained by the above-described reactions may in each case, if desired and/or necessary, be purified and/or isolated by customary methods known to those skilled in the art. Suitable purification processes are, for example, extraction processes and chromatographic processes such as column chromatography or preparative chromatography. All of the aforementioned process steps, and in each case also the purification and/or isolation of intermediates or end products, can be performed partly or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.
• inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formulae I and Ia referred to hereinafter only as 2,5-disubstituted thiazol-4-one derivatives of the general formula I, and corresponding stereoisomers, may be obtained in the form of their free bases, of their free acids or else in the form of corresponding salts, especially physiologically compatible salts.
• the free bases of the particular inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I and corresponding stereoisomers may, for example, be converted to the corresponding salts, preferably physiologically compatible salts, by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid.
• an inorganic or organic acid preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succ
• the free acids of the 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I and corresponding stereoisomers can be converted to the corresponding physiologically compatible salts by reaction with a suitable base.
• inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I and corresponding stereoisomers may optionally, just like the corresponding acids, the corresponding bases or salts of these compounds, also be obtained in the form of their solvates, preferably in the form of their hydrates, by customary methods known to those skilled in the art.
• inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I after they have been prepared, are obtained in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their different enantiomers and/or diastereomers, they can be separated and optionally isolated by customary processes known to those skilled in the art. Examples include chromatographic separation processes, especially liquid chromatography processes under standard pressure or under elevated pressure, preferably MPLC and HPLC processes, and processes for fractional crystallization.
• the present invention therefore further provides a medicament comprising at least one inventive 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, in each case optionally in the form of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of a mixture of stereoisomers, especially of the enantiomers and/or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically compatible excipients.
• inventive medicaments are suitable especially for vanilloid receptor 1 (VR1/TRPV1) regulation, especially for vanilloid receptor 1 (VR1/TRPV1) inhibition or for vanilloid receptor 1 stimulation.
• inventive medicaments are likewise suitable with preference for prophylaxis and/or treatment of disorders or diseases which are mediated at least partly by vanilloid receptors 1.
• the inventive medicament is therefore particularly suitable for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; for prophylaxis and/or treatment of one or more disorders selected from the group consisting of migraine; depression; urine incontinence; coughing; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease; Alzheimer's disease and multiple sclerosis; disorders of food uptake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; states of anxiety; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; diarrhea and pruritus; for prophylaxis and/or treatment of alcohol and/or drug and/or medicament abuse and alcohol and/or drug and/or medicament dependence, preferably for prophylaxis and/or reduction of withdrawal symptoms in the case of alcohol and/or drug and/or medicament dependence; for prophylaxis and/
• the inventive medicament is therefore particularly preferably suitable for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; for prophylaxis and/or treatment of one or more disorders selected from the group consisting of migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; states of anxiety; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; for prophylaxis and/or treatment of alcohol and/or drug and/or medicament abuse and alcohol and/or drug and/or medicament dependence, preferably for prophylaxis and/or reduction of withdrawal symptoms in the case of alcohol and/or drug and/or medicament dependence; for prophylaxis and/or reduction of evolution of tolerance to medicaments, especially medicaments based on opioids.
• pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic
• the inventive medicament is very particularly suitable for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain.
• the inventive medicament is suitable for administration to adults and children, including infants and babies.
• the inventive medicament may be present as a liquid, semisolid or solid medicament form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed to tablets, filled into capsules or suspended in a liquid, and may also be administered as such.
• the inventive medicament typically comprises further physiologically compatible pharmaceutical assistants which may, for example, be selected from the group consisting of carrier materials, fillers, solvents, diluents, surfactants, dyes, preservatives, disintegrants, lubricants, aromas and binders.
• physiologically compatible assistants and the amounts thereof to be used depends upon whether the medicament is to be administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to infections on the skin, the mucous membranes and in the eyes.
• suitable formulations are preferably those in the form of tablets, coated tablets, capsules, granules, pellets, drops, juices and syrups;
• suitable formulations for parenteral, topical and inhalative application are preferably solutions, suspensions, readily reconstitutable dry formulations and sprays.
• inventive 2,5-disubstituted thiazol-4-one derivatives used in the inventive medicament, in a depot, in dissolved form or in a plaster, optionally with addition of skin penetration-promoting agents, are suitable percutaneous administration formulations. Orally or percutaneously applicable formulation forms may also release the particular inventive 2,5-disubstituted thiazol-4-one derivative in a retarded manner.
• inventive medicaments are produced with the aid of conventional means, apparatus, methods and processes known from the prior art, as described, for example, in “Remington's Pharmaceutical Sciences”, editor A. R. Gennaro, 17th edition, Mack Publishing Company, Easton, Pa., 1985, more particularly in part 8, chapter 76 to 93. The corresponding description is hereby included as a reference and forms part of the disclosure.
• the amount of the particular inventive 2,5-disubstituted thiazol-4-one derivatives of the above-specified general formula I to be administered to the patient may vary and is, for example, dependent on the weight or age of the patient and of the administration method, the indication and the severity of the disorder. Typically, from 0.001 to 100 mg/kg, preferably from 0.05 to 75 mg/kg, more preferably from 0.05 to 50 mg/kg, of body weight of the patient of at least one such inventive compound are administered.
• the agonistic or antagonistic action of the substances to be studied on the vanilloid receptor 1 (VR1/TRPV1) of the rat species can be determined with the following assay.
• the Ca 2+ current through the receptor channel is quantified with the aid of a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
• HAMS F12 Nutrient Mixture (Gibco Invitrogen GmbH, Düsseldorf, Germany) with 10% by volume of FCS (fetal calf serum, Gibco Invitrogen GmbH, Düsseldorf, Germany, heat-inactivated);
• AA solution antioxidant/antimycotic solution, PAA, Pasching, Austria
• NGF medium 2.5 S, Gibco Invitrogen GmbH, Düsseldorf, Germany
• Cell culture plate poly-D-lysine-coated, black 96-hole plates with a clear bottom (96 well black/clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Düsseldorf, Germany) by diluting laminin to a concentration of 100 ⁇ g/ml with PBS (Ca—Mg-free PBS, Gibco Invitrogen GmbH, Düsseldorf, Germany). Aliquots having a concentration of 100 ⁇ g/ml of laminin are withdrawn and stored at ⁇ 20° C.
• the aliquots are diluted with PBS in a ratio of 1:10 to 10 ⁇ g/ml of laminin and in each case 50 ⁇ l of the solution are pipetted into a well of the cell culture plate.
• the cell culture plates are incubated at 37° C. for at least two hours, the supernatant solution is removed by suction and the wells are each washed twice with PBS.
• the coated cell culture plates are stored with supernatant PBS which is not removed until directly before the application of the cells.
• the spinal column is removed from beheaded rats and placed directly into cold HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany), i.e. placed in an ice bath, which has been admixed with 1% by volume of an AA solution (antibiotic/antimycotic solution, PAA, Pasching, Austria).
• AA solution antibiotic/antimycotic solution, PAA, Pasching, Austria.
• the spinal column is severed longitudinally and removed from the spinal canal together with fasciae. Subsequently, the dorsal root ganglia (DRGs) are removed and in turn stored in cold HBSS buffer admixed with 1% by volume of an AA solution.
• DDGs dorsal root ganglia
• the DRGs freed completely of blood residues and spinal nerves are in each case transferred to 500 ⁇ l of cold type 2 collagenase (PAA, Pasching, Austria) and incubated at 37° C. for 35 minutes. After addition of 2.5% by volume of trypsin (PAA, Pasching, Austria), incubation is continued at 37° C. for a further 10 minutes. After complete incubation, the enzyme solution is cautiously pipetted off and the remaining DRGs are each suspended with 500 ⁇ l of complete medium.
• PAA cold type 2 collagenase
• trypsin PAA, Pasching, Austria
• the DRGs are each suspended repeatedly, drawn through cannulas No. 1, No. 12 and No. 16 by means of a syringe and transferred to 50 ml Falcon tubes which are made up to 15 ml with complete medium. The contents of each Falcon tube are in each case filtered through a 70 ⁇ m Falcon filter insert and centrifuged at 1200 revolutions and room temperature for 10 minutes. The resulting pellet is in each case taken up in 250 ⁇ l of complete medium and the cell count is determined.
• the number of cells in the suspension is adjusted to 3 times 10 5 per ml and in each case 150 ⁇ l of this suspension are added to one well of the cell culture plates coated as described above. In the incubator, the plates are left to stand at 37° C., 5% by volume of CO 2 and 95% relative air humidity for two to three days.
• the cells are laden with 2 ⁇ M Fluo-4 and 0.01% by volume of Pluronic F127 (Molecular Probes Europe BV, Leiden, the Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) at 37° C. for 30 min, washed 3 ⁇ with HBSS buffer and, after a further incubation of 15 minutes, used in the FLIPR assay at room temperature for Ca 2+ measurement.
• the quantification is effected by the measurement of the highest fluorescence intensity (FC, fluorescence counts) over the time.
• the FLIPR protocol consists of 2 substance additions. First, the compounds to be tested (10 ⁇ M) are pipetted onto the cells and the Ca 2+ current is compared with the control (capsaicin 10 ⁇ M). This gives rise to the result in % activation based on the Ca 2+ signal after addition of 10 ⁇ M capsaicin (CP). After incubation for 5 minutes, 100 nM capsaicin is applied and the current of Ca 2+ is likewise determined.
• the agonistic or antagonistic action of the substances to be tested on vanilloid receptor (VR1) can also be determined with the assay which follows.
• the Ca 2+ current through the channel is quantified with the aid of a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes, Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
• FLIPR fluorescent imaging plate reader
• CHO K1 cells Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC) Great Britain) are transfected stably with the VR1 gene. For functional studies, these cells are plated out onto poly-D-lysine-coated black 96-well plates with a clear bottom (BD Biosciences, Heidelberg, Germany) in a density of 25 000 cells/well. The cells are incubated overnight at 37° C. and 5% CO 2 in a culture medium (Ham's Nutrient Mixture F12, 10% by volume of FCS (fetal calf serum), 18 ⁇ g/ml of L-proline).
• FCS fetal calf serum
• Fluo-4 Fluo-4 2 ⁇ M, Pluronic F127 0.01% by volume, Molecular Probes in HBSS (Hank's buffered saline solution), Gibco Invitrogen GmbH, Düsseldorf, Germany) at 37
• the FLIPR protocol consists of 2 substance additions. First, the substances to be tested (10 ⁇ M) are pipetted onto the cells and the Ca current is compared with the control (capsaicin 10 ⁇ M) (% activation based on the Ca 2+ signal after addition of 10 ⁇ M capsaicin). After incubation for 5 minutes, 100 nM capsaicin is applied and the current of Ca 2+ is likewise determined.
• the test to determine the antinociceptive action of the inventive 2,5-disubstituted thiazol-4-one derivatives is carried out in the formalin test on male mice (NMRI, body weight from 20 to 30 g, Iffa, Credo, Belgium).
• the inventive 2,5-disubstituted thiazol-4-one derivatives are tested in the second phase of the formalin test in order to obtain statements regarding substance effects on chronic/inflammatory pain.
• the administration time of the inventive 2,5-disubstituted thiazol-4-one derivatives before the formalin injection is selected.
• the intravenous administration of 10 mg/kg of body weight of the test substances is effected 5 minutes before the formalin injection. This is done by a single subcutaneous formalin injection (20 ⁇ l, 1% aqueous solution) into the dorsal side of the right hind paw, such that a nociceptive reaction is induced in freely mobile test animals, which is manifested in obvious licking and biting of the paw affected.
• the nociceptive behavior is registered continuously by observing the animals.
• the pain behavior is quantified by summation of the seconds in which the animals exhibit licking and biting of the paw affected within the test period.
• control animals which, instead of the inventive compounds, receive vehicle (0.9% aqueous sodium chloride solution) before formalin administration. Based on the quantification of the pain behavior, the substance action in the formalin test is determined as the change relative to the corresponding control in percent.
• mice Male NMRI mice with a weight of from 25 to 30 g were used. Groups of 10 animals per compound dose received, 10 minutes after intravenous administration of the compounds to be tested, 0.3 ml/mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, from Sigma, Deisenhofen, Germany; preparation of the solution with addition of 5% by weight of ethanol and storage in a water bath at 45° C.) which was applied intraperitoneally. The animals were placed individually into observation cages.
• phenylquinone phenylbenzoquinone
• the stationary phase used for the column chromatography was silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt.
• the analysis was effected by mass spectroscopy and NMR.
• the mother liquor was reduced further down to 75 ml and cooled.
• Cyanomorpholine (15.3 g, 136.3 mmol) and thioglycolic acid (12.5 g, 136.3 mmol) were introduced into a reaction vessel with pyridine (12.2 ml).
• the reaction vessel was heated to 10° C. in a Pyrex tube. After one hour, the reaction was ended and the mixture was cooled.
• 1,1′-Thiocarbonyldiimidazole (45.4 g, 254 mmol) was suspended in THF (605 g).
• Thiomorpholine 25 g, 242.6 mmol was dissolved in a little THF and added to the suspension.
• the reaction mixture was stirred at RT for 1 h.
• 7 N ammonia solution in MeOH (346 g) was added thereto and the reaction mixture was stirred at 40° C. overnight.
• the solvent was removed under reduced pressure, and the residue was washed with a little cold butanol and ether and dried.
• the desired product was obtained in an amount of 31.5 g.
• 1,1′-Thiocarbonyldiimidazole (3.8 g, 21.2 mmol) was suspended in THF (23.4 g).
• 1-(3-Chloropyridin-2-yl)piperazine (4 g, 20.2 mmol) was dissolved in a little THF and added to the suspension.
• the reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (28.9 g) was added thereto and the reaction mixture was stirred at 40° C. overnight.
• the solvent was removed under reduced pressure, and the residue was washed with a little cold butanol and ether and dried.
• the desired product was obtained in an amount of 4.1 g (78% of theory).
• 1,1′-Thiocarbonyldiimidazole (18 g, 101.2 mmol) was suspended in THF (112 g). 1-Benzylpiperazine (17 g, 96.5 mmol) was dissolved in a little THF and added to the suspension. The reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (137 g) was added thereto and the reaction mixture was stirred at 40° C. overnight. The solvent was removed under reduced pressure, and the residue was heated in a little butanol (25 ml). After cooling, a precipitate was obtained, which was washed with a little cold butanol and ether and then dried. The desired product was obtained in an amount of 14.1 g.
• 1,1′-Thiocarbonyldiimidazole (12.5 g, 70.4 mmol) was suspended in THF (167 g). 4-tert-Butylaniline (10 g, 67 mmol) was dissolved in a little THF and added to the suspension. The reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (95 g) was added thereto and the reaction mixture was stirred at 40° C. for 48 h. The solvent was removed under reduced pressure and the residue was heated in a little butanol (25 ml). After cooling, a precipitate was obtained, which was washed with a little cold butanol and ether and then dried. The desired product was obtained in an amount of 14 g.
• 1,1′-Thiocarbonyldiimidazole (12.3 g, 69.5 mmol) was suspended in THF (167 g). 3,4-Methylenedioxybenzylamine (10 g, 66.2 mmol) was dissolved in a little THF and added to the suspension. The reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (94.5 g) was added thereto and the reaction mixture was stirred at 40° C. for 24 h. The solvent was removed under reduced pressure and the residue was heated in a little butanol (15 ml). After cooling, a precipitate was obtained, which was washed with a little cold butanol and ether and then dried. The desired product was obtained in an amount of 11.1 g (80% of theory).
• Benzo[1.3]dioxol-5-ylmethylthiourea (11 g, 52.4 mmol) was suspended with chloroacetic acid (5.1 g, 54.4 mol) in pyridine (20 g). The suspension was heated to 110° C. in a microwave vessel for 60 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved with a little butanol (15 ml) while heating. After cooling, a precipitate formed, which was filtered off with suction, washed with a little butanol and diisopropyl ether and dried. The desired product was obtained as a solid (4.0 g, 30% of theory).

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